Vascular deposition of amyloid beta peptide (Abeta) occurs during normal aging and is accelerated in Alzheimer's disease (AD). Abeta is considered to be implicated in the cerebrovascular pathology in AD and related disorders such as hereditary cerebral hemorrhage with amyloidosis of Dutch type, a form of cerebral amyloid angiopathy (CAA). Recent studies suggest a major role for the blood-brain barrier (BBB) and cerebrospinal fluid (CSF) clearance in regulating the concentrations of soluble Abeta in cerebral vasculature and brain. Our preliminary data indicate that glycoprotein 330 the 'receptor for advanced glycation and products' (RAGE), scavenger receptor, and yet molecularly non-identified receptor(s)/transporter(s) participate in endothelial binding and/or BBB transcytosis of free and/or bound form of Abeta. Preliminary finding suggest enhanced Abeta endothelial binding and BB transport in the brain of senescent non-human primates and in AD. We propose to use senescent non-human primates, in vitro BB model, and transgenic (Tg) CAA (Dutch type, wild) AND Tg vascular RAGE mice to test the hypothesis that aging predisposes to cerebrovascular and parenchymal accumulation and deposition of Abeta by upsetting the balance between transport of Abeta across the BB, its metabolism and clearance from brain and CSF, and this is further enhanced by the presence of CC and over-expression of vascular RAGE. We will determine in vivo pharmacokinetics, BBB permeability and microvascular-accumulation (aim 1) and clearance from brain and CSF (aim 2) of Abeta in aged versus adult non-human primates. Aim 3 is molecular characterization and isolation of Abeta brain endothelial receptors/transporters in an in vitro BB model in non-human primates and humans (controls, AD). In aim 4 we will determine blood-to-brain transport and vascular sequestration, and in aim 5 brain and CSF clearance of Abeta in Tg CAA, Tg vascular RAGE and crossed Tg CAA/RAGE mice. Proposed studies will define the roles of circulating and brain-derived Abeta in the development of cerebrovascular amyloidosis, and provide the molecular basis for new therapeutic strategies to prevent cerebrovascular Abeta accumulation, amyloid formation and their pathogenic effects on the vascular system and brain.